Thrombosis in the Uremic Milieu—Emerging Role of “Thrombolome”

Chronic kidney disease (CKD) is characterized by retention of a number of toxins, which unleash cellular damage. CKD environment with these toxins and a host of metabolic abnormalities (collectively termed as uremic milieu) is highly thrombogenic. CKD represents a strong and independent risk factor for both spontaneous venous and arterial (postvascular injury) thrombosis. Emerging evidence points to a previously unrecognized role of some of the prothrombotic uremic toxins. Here, we provide an overview of thrombosis in CKD and an update on indolic uremic toxins, which robustly increase tissue factor, a potent procoagulant, in several vascular cell types enhancing thrombosis. This panel of uremic toxins, which we term “thrombolome” (thrombosis and metabolome), represents a novel risk factor for thrombosis and can be further explored as biomarker for postvascular interventional thrombosis in patients with CKD.     

Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction

Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium-dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia-specific factors. Several uremic toxins, mostly protein-bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p-cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro-oxidant and pro-inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein-bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.     

Renal disease in recipients of nonrenal solid organ transplantation

Worldwide, more than 250,000 individuals who have received a liver, heart, lung, or intestinal transplant are living longer. Twenty percent to 25% of these recipients experience perioperative acute renal failure, with 10% to 15% requiring renal replacement therapy. Chronic kidney disease (CKD) is also highly prevalent, affecting 30% to 50% of the nonrenal organ transplant population with an annual end-stage renal disease risk of 1.5% to 2.0%. Both acute renal failure and CKD contribute to increased morbidity and premature mortality. The dominant causative factor for renal disorders seen in nonrenal transplant recipients are the calcineurin inhibitors (CNI) and rapamycin analogues, which singly or in combination lead to a variety of nephrotoxic injury. However, 25% to 30% of nonrenal transplant recipients with CKD have other conditions such as hypertension, focal segmental glomerulosclerosis, diabetes mellitus, and hepatitis C infection as the principal underlying cause. Management strategies for renal disease in the nonrenal transplant recipients include the following: (1) delayed introduction of CNI after graft implantation, (2) withdrawal or minimization of long-term CNI therapy, (3) timely use of an appropriate dialysis modality, and (4) expeditious introduction of supportive measures such as anemia management, phosphate binding therapy, and dietary modification. Compared with maintenance dialysis, kidney transplantation reduces long-term mortality by 60% to 70% in nonrenal transplant recipients with end-stage renal disease.     

Acute kidney injury as a risk factor for chronic kidney diseases in disadvantaged populations

Acute kidney injury (AKI) is considered to be a potential cause for developing chronic kidney disease (CKD); on the other hand, CKD predisposes to AKI. The lack of adequate epidemiological data makes it difficult to determine if AKI induces CKD in less developed countries. The etiology of AKI in rich populations, in whom sophisticated surgery, interventional radiology and oncology treatments are usually the cause of AKI, is very different from that of disadvantaged populations, where the origin of AKI is associated with endemic infections, obstetric problems, poisons, toxins and natural disasters. Any conclusions extrapolated from these two settings should be treated with caution. Moreover, people living in disadvantaged conditions are usually much younger than those in rich areas and this age factor could facilitate total recovery of renal function after AKI if treatment based on an adequate supply of water, rehydration and anti-infectious measures were provided. In the small segment of the population of less developed countries having an income per capita similar to that observed in the developed countries, the long-term outcome of AKI should also be expected to be similar. New data coming from two single centers analyzing only the long-term outcome of acute tubular necrosis (ATN) patients, with a normal or near normal renal function prior to the AKI episode, coincide in reporting a requirement for chronic dialysis among the surviving patients of 2%. If these data are confirmed, the importance of AKI as cause of CKD should be reconsidered, both in developed and less developed countries.     

Remote ischaemic pre‐conditioning for the prevention of acute kidney injury

Acute kidney injury (AKI) is a common complication associated with high morbidity and mortality in hospitalized patients. One potential mechanism underlying renal injury is ischaemia/reperfusion injury (IRI), which attributed the organ damage to the inflammatory and oxidative stress responses induced by a period of renal ischaemia and subsequent reperfusion. Therapeutic strategies that aim at minimizing the effect of IRI on the kidneys may prevent AKI and improve clinical outcomes significantly. In this review, we examine the technique of remote ischaemic preconditioning (rIPC), which has been shown by several trials to confer organ protection by applying transient, brief episodes of ischaemia at a distant site before a larger ischaemic insult. We provide an overview of the current clinical evidence regarding the renoprotective effect of rIPC in the key clinical settings of cardiac or vascular surgery, contrast‐induced AKI, pre‐existing chronic kidney disease (CKD) and renal transplantation, and discuss key areas for future research.     

Patterns of kidney injury in pediatric nonkidney solid organ transplant recipients

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKI and CKD and examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKI was assessed in the first year posttransplant. Among 303 children, perioperative AKI (within the first week) occurred in 67% of children, and AKI after the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty‐three children (8%) developed CKD after a median follow‐up of 3.4 years. Less than 5 children developed end‐stage renal disease, all within 65 days posttransplant. Those with 1 AKI episode by 3 months posttransplant had significantly greater risk for developing CKD after adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13‐6.80, P trend = .008). AKI is common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney‐sparing strategies to decrease risk for progression to CKD.     

Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis

The effectiveness of cisplatin, a mainstay in the treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes AKI in 30% of patients. Patients who do not develop AKI by clinical standards during treatment are still at risk for long-term decline in kidney function and the development of CKD. The connection between AKI and CKD has become increasingly studied, with renal fibrosis a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both, are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. The use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.     

Removal of Protein‐Bound,Hydrophobic Uremic Toxins by a Combined Fractionated Plasma Separation and Adsorption Technique

Protein‐bound uremic toxins, such as phenylacetic acid, indoxyl sulfate, and p‐cresyl sulfate, contribute substantially to the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD). However, based on their protein binding, these hydrophobic uremic toxins are poorly cleared during conventional dialysis and thus accumulate in CKD‐5D patients. Therefore, we investigated whether hydrophobic and cationic adsorbers are more effective for removal of protein‐bound, hydrophobic uremic toxins than conventional high‐flux hemodialyzer. Five CKD‐5D patients were treated using the fractionated plasma separation, adsorption, and dialysis (FPAD) system for 5 h. A control group of five CKD patients was treated with conventional high‐flux hemodialysis. Plasma concentrations of phenylacetic acid, indoxyl sulfate, and p‐cresyl sulfate were measured. Removal rates of FPAD treatment in comparison to conventional high‐flux hemodialysis were increased by 130% for phenylacetic acid, 187% for indoxyl sulfate, and 127% for p‐cresol. FPAD treatment was tolerated well in terms of clinically relevant biochemical parameters. However, patients suffered from mild nausea 2 h after the start of the treatment, which persisted until the end of treatment. Due to the high impact of protein‐bound, hydrophobic uremic toxins on progression of CKD and CVD in CKD‐5D patients, the use of an adsorber in combination with dialysis membranes may be a new therapeutic option to increase the removal rate of these uremic toxins. However, larger, long‐term prospective clinical trials are needed to demonstrate the impact on clinical outcome.     

Biomarkers of acute kidney injury

The diagnosis of acute kidney injury (AKI) is usually based on measurements of blood urea nitrogen (BUN) and serum creatinine. BUN and serum creatinine are not very sensitive or specific for the diagnosis of AKI because they are affected by many renal and nonrenal factors that are independent of kidney injury or kidney function. Biomarkers of AKI that are made predominantly by the injured kidney have been discovered in preclinical studies. In clinical studies of patients with AKI, some of these biomarkers (eg, interleukin-18, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1) have been shown to increase in the urine before the increase in serum creatinine. These early biomarkers of AKI are being tested in different types of AKI and in larger clinical studies. Biomarkers of AKI may also predict long-term kidney outcomes and mortality.     

Lung injury following acute kidney injury: kidney–lung crosstalk

The mortality of acute kidney injury (AKI) remains unacceptably high, especially associated with acute respiratory failure. Lung injury complicated with AKI was previously considered as “uremic lung”, which is characterized by volume overload and increased vascular permeability. New experimental data using rodent models of renal ischemia–reperfusion and bilateral nephrectomy have emerged recently focusing on kidney–lung crosstalk in AKI, and have highlighted the pathophysiological significance of increased cytokine concentration, enhanced inflammatory responses, and neutrophil activation. In this review, we outline the history of uremic lung and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), the epidemiological data on the synergistic effect of AKI and lung injury on mortality, and recent basic research which has identified possible pathways in AKI-induced lung injury. These findings will enable us to develop new therapeutic strategies against lung injury associated with AKI and improve the outcomes of critically ill patients in intensive care units.     

Uremic toxins: some thoughts on acrolein and spermine

Chronic kidney disease (CKD) is characterized by the progressive reduction of glomerular filtration rate and subsequent retention of organic waste compounds called uremic toxins. While patients with CKD are at a higher risk of premature death due to cardiovascular complications, this increased risk cannot be completely explained by classical cardiovascular risk factors such as hypertension, diabetes mellitus, and obesity. Instead, recent research suggests that uremic toxins may play a key role in explaining this marked increase in cardiovascular mortality in patients with CKD. While spermine, a tetra-amine, has previously been hypothesized to act as an uremic toxin, the following review presents a summary of recent literature that casts doubt on this assertion. Instead, acrolein, an oxidative product of spermine and the triamine spermidine, is likely responsible for the toxic effects previously attributed to spermine.     

Acute kidney injury in childhood: should we be worried about progression to CKD?

While emerging evidence indicates that the incidence of both acute kidney injury (AKI) and chronic kidney disease (CKD) in children is rising and that the etiologies are dramatically changing, relatively little is currently known regarding the potential for transition from AKI to CKD. Major barriers to assessing for a potential AKI to CKD link have included lack of a standard pediatric AKI definition, narrow focus only on children with AKI who receive renal replacement therapy, and reliance on serum creatinine as the main biomarker to detect and diagnose AKI and CKD. Recent data have validated a multi-dimensional AKI classification system for children and have suggested chronic kidney sequelae in pediatric populations with AKI or at risk for AKI. In addition, a number of novel AKI biomarkers are being rigorously validated as early indicators of incipient CKD. Our goals for this article are to (1) review the recent changes in pediatric AKI and CKD epidemiology, (2) explore the evidence for a potential AKI to CKD link, and (3) propose new clinical and research paradigms to better elucidate the progression from AKI to CKD.     

Acute kidney injury: changing lexicography, definitions, and epidemiology

In recent years, there have been numerous advances in understanding the molecular determinants of functional kidney injury after ischemic and/or toxic exposure. However, translation of successful novel therapies designed to attenuate kidney functional injury from animal models to the clinical sphere has had modest results. This lack of translatability is at least in part due to lack of sufficient standardization in definitions and classification of cases of acute kidney injury (AKI), an incomplete understanding of the natural history of human AKI, and a limited understanding of how kidney injury interacts with other organ system failure in the context of systemic metabolic abnormalities. A concerted effort is now being made by nephrologists and intensivists to arrive at standardized terminology and classification of AKI. There have also been dramatic advances in our understanding of the epidemiology and natural history of AKI, particularly in the hospital and intensive care unit setting. Promising strategies are now being developed which may ultimately lead to improved outcomes for patients at risk for or who have developed AKI, which should be readily testable in the coming decade.     

Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis

Acute kidney injury may increase the risk for chronic kidney disease and end-stage renal disease. In an attempt to summarize the literature and provide more compelling evidence, we conducted a systematic review comparing the risk for CKD, ESRD, and death in patients with and without AKI. From electronic databases, web search engines, and bibliographies, 13 cohort studies were selected, evaluating long-term renal outcomes and non-renal outcomes in patients with AKI. The pooled incidence of CKD and ESRD were 25.8 per 100 person-years and 8.6 per 100 person-years, respectively. Patients with AKI had higher risks for developing CKD (pooled adjusted hazard ratio 8.8, 95% CI 3.1-25.5), ESRD (pooled adjusted HR 3.1, 95% CI 1.9-5.0), and mortality (pooled adjusted HR 2.0, 95% CI 1.3-3.1) compared with patients without AKI. The relationship between AKI and CKD or ESRD was graded on the basis of the severity of AKI, and the effect size was dampened by decreased baseline glomerular filtration rate. Data were limited, but AKI was also independently associated with the risk for cardiovascular disease and congestive heart failure, but not with hospitalization for stroke or all-cause hospitalizations. Meta-regression did not identify any study-level factors that were associated with the risk for CKD or ESRD. Our review identifies AKI as an independent risk factor for CKD, ESRD, death, and other important non-renal outcomes.     

Perioperative management of the patient with chronic kidney disease

The prevalence of chronic kidney disease (CKD) is increasing. Perioperative management of patients with CKD aims to control modifiable risk factors associated with acute kidney injury (AKI). AKI on the background of CKD may lead to dialysis dependency. CKD has widespread cardiovascular, endocrine, metabolic and haematological effects. Preoperative assessment and preparation require multidisciplinary input from the surgical, anaesthetic and nephrology teams. Perioperative care should ensure the correction of hypovolaemia, maintenance of renal blood flow and perfusion pressure, prevention of radiocontrast-induced nephrotoxicity, avoidance of nephrotoxic drugs and treatment of urinary tract obstruction.     

Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis–mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.     

Discovering novel injury features in kidney transplant biopsies associated with TCMR and donor aging

We previously characterized the molecular changes in acute kidney injury (AKI) and chronic kidney disease (CKD) in kidney transplant biopsies, but parenchymal changes selective for specific types of injury could be missed by such analyses. The present study searched for injury changes beyond AKI and CKD related to specific scenarios, including correlations with donor age. We defined injury using previously defined gene sets and classifiers and used principal component analysis to discover new injury dimensions. As expected, Dimension 1 distinguished normal vs. injury, and Dimension 2 separated early AKI from late CKD, correlating with time posttransplant. However, Dimension 3 was novel, distinguishing a set of genes related to epithelial polarity (e.g., PARD3) that were increased in early AKI and decreased in T cell–mediated rejection (TCMR) but not in antibody-mediated rejection. Dimension 3 was increased in kidneys from older donors and was particularly important in survival of early kidneys. Thus high Dimension 3 scores emerge as a previously unknown element in the kidney response-to-injury that affects epithelial polarity genes and is increased in AKI but depressed in TCMR, indicating that in addition to general injury elements, certain injury elements are selective for specific pathologic mechanisms. (ClinicalTrials.gov NCT01299168).     

Acute kidney injury and chronic kidney disease: an integrated clinical syndrome

The previous conventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renal function appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase the risk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKD is an important risk factor for the development and ascertainment of AKI. Experimental data support the clinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions in renal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repair mechanisms appear to be important modulators of progression in patients with and without coexistent CKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integrated clinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state and outcome is determined by host factors, including the balance of adaptive and maladaptive repair mechanisms over time. Physicians must provide long-term follow-up to patients with first episodes of AKI, even if they presented with normal renal function.